API and IP Newsletter
Contents
FDA approval in January 2023: Pirtobrutinib
We follow FDA approvals in this newsletter, small molecules. We analyse brief chemistry; we report patent families filed by innovator. There is high likelihood that US equivalents of these families could be listed in Orange Book. We then try to understand active generic players in India in this molecule, based on IP filed by the generic companies or intermediates being imported by these generic players. Depending upon the quantities ordered and timing of import these raw materials/KSMs, we estimate development status of the molecule in laboratories of generic companies.
Eli Lilly and Company, on 27 January 2023 announced that the FDA approved Jaypirca™ (pirtobrutinib), which is a kinase inhibitor
It is an orally available, small molecule ATP-competitive inhibitor of BTK (Bruton’s tyrosine kinase).
The chemical name for pirtobrutinib is 5-amino-3-{4-[(5-fluoro-2-methoxybenzamido) methyl] phenyl}-1-[(2S)-1,1,1- trifluoropropan-2-yl]-1H-pyrazole-4-carboxamide.
Pirtobrutinib is a white to practically white to yellow to brown solid.
The aqueous solubility of pirtobrutinib is considered practically insoluble, or insoluble, across the pH 1 to pH 7 range.
Pirtobrutinib tablets are supplied as 50 mg or 100 mg film-coated, debossed tablets for oral administration. Each tablet contains inactive ingredients of croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose and silicon dioxide.
The tablet film coating material contains FD&C Blue #2, hypromellose, titanium dioxide and triacetin.
One would need KSM 5-amino-l-[(lS)-2,2,2-trifluoro-l-methyl-ethyl] pyrazole-4 carbonitrile to synthesise Pirtobrutinib.
To prepare this KSM one could start from [(lS)-2,2,2-Trifluoro-l-methyl-ethyl] hydrazine hydrochloride. Aurigene and Chempure are importing this RM in small quantities.
Indian companies have already started development of this API and they could be in the first phase of API development.
One of the reported processes is as below:
Important patent families are as follows:
WO 2017/103611: Patent family filed by Redx Pharma Plc relates to compound claims
WO 2020/028258: Patent family filed by Loxo Oncology, Inc. relates to pharmaceutical composition
WO2022056100A1: Patent family filed by filed by Loxo Oncology, Inc. and relates to Intermediates and process.
One could have question, why there are different IP owners for the different patent families of pirtobrutinib of Eli Lilly?
Please note, Redx program for the Bruton’s tyrosine kinase (BTK) inhibitor was sold to Loxo Oncology (now part of Eli Lilly) in July 2017 for $40 million, and one of the lead compounds, pirtobrutinib (originally RXC005, then LOXO-305, now JaypircaTM) has been approved by FDA.
Redx is not due to receive any future payments in relation to RXC005. Here.
This explains different IP owners for different patent families of Eli Lilly’s pirtobrutinib.
General information
Drug prices 'not justified' by pharma R&D spending, new study says
The researchers question the claim that high drug prices are needed to sustain valuable innovation by analyzing publicly available financial reports from 1999 to 2018 at the 15 largest biopharmaceutical companies.
According to the paper, companies spent more on selling, general, and administrative activities, including marketing, than on R&D — every year from 1999 to 2018.
News here.
Pharma Adoption of Data Analytics
Adoption of data analytics in the pharma industry has been slower than in other industries, says Andrew Lo, PhD, Charles E. and Susan T. Harris professor, a professor of finance, and the director of the Laboratory for Financial Engineering at the MIT Sloan School of Management. In research over the last decade, the Lo team has shown how data science, using scores of factors, can more accurately predict a drug’s approval success.
But back to the 3.6 million data points. According to the 20-80 breakdown, a little math shows that if 720,000 data points are analyzed and 2.8 million remain warehoused, a lot of data is left on the cutting room floor.
News here.
Intellectual Property
Cabozantinib (Cabometyx®)- Exelixis Vs MSN in The United States District Court for the District of Delaware
Last week we discussed the same case, but it was related to another OB listed patent, ie `473.
The readers would recall this litigation is about two patents listed in OB, viz '473 and '776 for Cabometyx®.
The '473 patent discloses compounds including cabozantinib that are tyrosine kinase inhibitors (TKIs).
The '776 patent is directed to a particular crystalline form of cabozantinib (L)-malate called Form N-2.
This write-up is confined to the `776 patent.
Claim 1 of the '776 patent states:
Cabozantinib (L )-malate salt, wherein said salt is in crystalline Form N-2 and said Form N-2 is characterized by at least one of the following: (i) solid state 13C NMR spectrum with four or more peaks selected from 23.0, 25.9, 38.0, 41.7, 69.7, 102.0, 122.5, 177.3, 179.3, 180.0, and 180.3, ±0.2 ppm; (ii) a powder x-ray diffraction pattern (Cu.Ka 11,=l.5418 A) comprising 20 values at 20.9±0.2 °20 and 21.9±0.2 °20, and two or more 20 values selected from: 6.4±0.2 0 20, 9.1±0.2 °20, 12.0±0.2 °20, 12.8±0.2, 13.7±0.2, 17.1±0.2, 22.6±0.2, 23.7±0.2, wherein measurement of the crystalline form is at room temperature; and/or (iii) an x-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG. 8.
It will be interesting to know how this Court had opined on non-infringement argument of MSN.
The Court considered the following facts, which are agreed by both parties.
MSN's active pharmaceutical ingredient ("API"), will be stored in well closed containers at 2 to 8°C temperature and protected from moisture.
The samples of MSN's API that Dr. Munson tested were three years old when he received them.
Dr. Munson's accelerated conditions are not representative of the prescribed storage conditions of MSN's API prior to tablet manufacturing.
MSN's API will be combined with excipients before the granulating, drying, and coating steps of MSN's tablet manufacturing begin.
Dr. Munson's accelerated conditions are not representative of the conditions that MSN's API will undergo during tablet manufacturing.
The product label for MSN's tablets will require storing cabozantinib at room temperature between 68°F to 77°F (20°C to 25°C).
Stability studies, such as those pursuant to the ICH guidelines are not always predictive of physical changes that compounds will experience over time.
Dr. Munson's accelerated conditions are not representative of the conditions that the ICH guidelines recommend for testing a new drug compound that should be refrigerated.
MSN performed stress testing on its API in the process of developing a manufacturing process. The conditions used by MSN in this testing are not representative of conditions that MSN's API or tablet will likely face.
Dr. Munson's 19F NMR testing of MSN's API using his accelerated conditions did not reasonably quantify the amount of Form N-2 that was initially present in MSN's API.
For infringement of claim 1 of the '776 patent, Exelixis must prove that Form N-2 will be detected in MSN's proposed ANDA product according to 13C NMR test criteria (limitation l(i)) and/or XRPD test criteria (limitations l(ii) or l(iii)).
The point of contention
MSN contended that its tablets will include only Form S of cabozantinib, where MSN formulated Form S as a design around for Form N-2.
Exelixis disagreed, argued that Form S is unstable and, over time, will convert to Form N-2, thus causing infringement.
What happened at trial?
At trial, Exelixis provided no direct evidence of 13C NMR or XRPD test results detecting Form N-2 in MSN's tablets.
Instead, Exelixis presented evidence that Dr. Munson detected Form N-2 in MSN's API through 13C NMR testing.
Dr. Munson's testing of MSN's API did not detect Form N-2 in MSN's three-year-old as-provided samples, however, Dr. Munson only detected Form N-2 in MSN's API after subjecting the test samples to accelerated conditions.
The parties disagreed whether Dr. Munson's accelerated conditions are representative of the conditions MSN's proposed ANDA product will likely face in the real world and, thus, if the corresponding test results are indicative of infringement of claim limitation l(i).
Exelixis explained that Dr. Munson subjected MSN's API to accelerated conditions of 40°C at 75% relative humidity ("RH") in an open container. Dr. Munson then performed 13C NMR testing on the conditioned API after four and eight weeks, and, in both tests, detected Form N-2.
Exelixis argued that Dr. Munson's 13C NMR testing of MSN's API after applying the accelerated conditions is representative of how the API will behave in the real world over time.
The Court found that Dr. Munson's results from using accelerated conditions are not representative of how MSN's API or tablets will behave in the real world over time.
There are significant differences between Dr. Munson's accelerated conditions and the conditions that MSN's API and tablets will face during manufacture and storage. First, the court found that Dr. Munson's accelerated conditions are not representative of the conditions that MSN's API will face during manufacture.
Exelixis argued that, during manufacture, MSN's API is exposed to 55-60°C under high humidity for ~8 hours.
Dr. Munson received samples of MSN's API that had already been manufactured and, thereby, had already been subjected to eight hours at 55 to 65 degrees C.
Thus, the Court found persuasive Dr. Steed's testimony that Form N-2 would already have been present in Dr. Munson's API samples if the API manufacturing conditions caused Form N-2 to form.
Second, the Court that Exelixis had not shown that Dr. Munson's accelerated conditions are representative of MSN's API storage conditions prior to tablet manufacturing.
While Dr. Munson let the API sit in open petri dishes at a high temperature and humidity, MSN's ANDA prescribes storing the API in well closed containers at 2 to 8°C temperature and protected from moisture.
In addition, the samples of MSN's API that Exelixis received were already three years old. Considering this, the Court found credible Dr. Steed's testimony that, absent the accelerated conditions, there's no reason to think that MSN's three-year old API samples would begin to convert to Form N-2 if it left to sit longer at the prescribed storage conditions.
So, this Court upheld non-infringement argument of MSN for `776. The Court concluded Exelixis failed to prove by a preponderance of the evidence that MSN will infringe claim 1 of the '776 patent
Decision here.
